title: ZIP14 zinc transporter downregulation and zinc depletion in the development and progression of hepatocellular cancer.
abstract: OBJECTIVE
  Hepatocellular cancer (HCC) is a deadly and most rapidly increasing cancer in the USA and worldwide. The etiology and factors involved in development of HCC remain largely unknown. A marked decrease in zinc occurs in HCC. Its role and involvement in HCC has not been identified. We investigated the relationship of cellular zinc changes to the development of malignancy, and the identification of potential zinc transporters associated with the inability of hepatoma cells to accumulate zinc.
  
  
  METHODS
  The detection of relative zinc levels in situ in normal hepatic cells vs. hepatoma was performed on normal and HCC tissue sections. ZIP1, 2, 3, and 14 transporters were identified by immunohistochemistry.
  
  
  RESULTS
  Intracellular zinc levels are markedly decreased in HCC hepatoma cells vs. normal hepatic cells in early stage and advanced stage malignancy. ZIP14 transporter is localized at the plasma membrane in normal hepatocytes, demonstrating its functioning for uptake and accumulation of zinc. The transporter is absent in the hepatoma cells and its gene expression is downregulated. The change in ZIP14 is concurrent with the decrease in zinc. ZIP1, 2, 3 are not associated with normal hepatocyte uptake of zinc, and HCC zinc depletion. HepG2 cells exhibit ZIP14 transporter. Zinc treatment inhibits their growth.
  
  
  CONCLUSIONS
  ZIP14 downregulation is likely involved in the depletion of zinc in the hepatoma cells in HCC. These events occur early in the development of malignancy possibly to protect the malignant cells from tumor suppressor effects of zinc. This provides new insight into important factors associated with HCC carcinogenesis.
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, MD 21201, USA. rfranklin@umaryland.edu
authors.forename: Renty B
authors.initials: RB
authors.lastname: Franklin
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Levy
authors.forename: Jing
authors.initials: J
authors.lastname: Zou
authors.forename: Nader
authors.initials: N
authors.lastname: Hanna
authors.forename: Mohamed Mokhtar
authors.initials: MM
authors.lastname: Desouki
authors.forename: Omar
authors.initials: O
authors.lastname: Bagasra
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Costello
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D046888:Tissue Array Analysis; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C497524:SLC39A14 protein, human; D015032:Zinc